Monoamine neurotransmitters have been implicated in the body's response to neurological disorders such as pain and depression. Norepinephrine (NE) and serotonin (5-HT) are monoamine neurotransmitters originating in the brain and projecting diffusely throughout the central nervous system. 5-HT and NE are reported to be involved in modulating pain transmission from the spinal cord to the brain and also governing the body's moods and responses to stress.
Depression refers to an abnormal mood or a collection of symptoms that constitute a psychiatric disorder. Symptoms of depression include disturbances in mood and affect (depressed mood, diminished interest and pleasure in activities), bodily function (weight and appetite changes, psychomotor disturbances, sleep disturbances, fatigue, and loss of energy), and cognitive processes (feelings of worthlessness and guilt, concentration difficulties, indecisiveness, thoughts of death or suicide, and possibly delusions/hallucinations). These symptoms vary in intensity, duration and frequency and permit classification of depression into different classes. Other symptoms of major depressive episodes include crying spells, self-pity, hopelessness, irritability, brooding, diminished self-esteem, decreased libido, nihilism, social withdrawal, memory impairment, feelings of inadequacy, and pessimism.
It has been reported that electrical stimulation of certain brain regions releases 5-HT and NE, which are believed to produce an analgesia in both animals and humans. Conversely, it has been reported that depletion of serotonin in the rat results in an enhanced response to pain. There also appears to be synergistic actions between NE and 5-HT in modulating pain sensation. Studies in the rat show that the analgesia from exogenously administered 5-HT can be blocked by depleting NE in the spinal cord.
Common antidepressants increase synaptic availability of biogenic amines by blocking their major means of physiological inactivation, which involves transport or reuptake into nerve terminals. Examples include “dual” action agents that inhibit the reuptake of both NE and 5-HT (e.g., venlafaxine and milnacipram), selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine and sertraline), and norepinephrine reuptake inhibitors (e.g., Reboxetine). A major drawback to all of these agents is the therapeutic lag associated with their use—patients must take the drug for up to 3 weeks to achieve clinically meaningful symptomatic relief. Furthermore, a significant number of patients do not respond to current therapies at all. For example, it is currently estimated that up to thirty percent (30%) of clinically diagnosed cases of depression are resistant to all forms of current drug therapy. Consequently, there is a significant need for effective treatments of various neurological disorders.